Epirubicin and Non-Muscle Invasive Bladder Cancer Treatment: A Systematic Review

(1) Background: Intravesical chemotherapy is the standard of care in intermediate-risk non-muscleinvasive bladder cancer (NMIBC). Different agents are used across the world based on availability, cost, and practice patterns. Epirubicin (EPI), one of these agents, has been used by many centers over many decades. However, its true differential efficacy compared to other agents and its tolerability are still poorly reported. We aimed to assess the differential efficacy and safety of intravesical EPI in NMIBC patients. (2) Methods: This study aimed to systematically review the efficacy and safety profile of Epirubicin (EPI) in the management of non-muscle invasive bladder cancer (NMIBC) compared to other adjuvant therapies. A systematic search of the PUBMED, Web of Science, clinicaltrials.gov, and Google Scholar databases was conducted on 31 December 2023, using relevant terms related to EPI, bladder cancer, and NMIBC. The inclusion criteria targeted studies that evaluated patients treated with EPI following the transurethral resection of bladder tumors (TURBT) for NMIBC and compared oncological outcomes such as recurrence and progression with other adjuvant therapies, including Mitomycin C (MMC), Gemcitabine (GEM), and Bacillus Calmette-Guérin (BCG). Additionally, studies investigating the safety profile of EPI administered intravesically at room temperature and under hyperthermia, as well as oncological outcomes associated with hyperthermic intravesical EPI administration, were included. (3) Results: Eleven studies reported adverse events after adjuvant intravesical instillations with EPI; the most frequently reported adverse events included cystitis (34%), dysuria, pollakiuria, hematuria, bladder irritation/spasms, fever, nausea and vomiting, and generalized skin rash (2.3%). Nine studies compared EPI to BCG in terms of recurrence and progression rates; BCG instillations showed a lower recurrence rate compared to EPI, with limited or non-significant differences in progression rates. Two studies found no significant differences between EPI and MMC regarding progression and recurrence rates. One study showed statistically significant lower recurrence and progression rates with GEM in high-risk NMIBC patients. Another study found no significant differences between EPI and GEM regarding recurrence and progression. (4) Conclusions: EPI exhibits similar oncological performances to Gemcitabine and Mitomycin C currently used for adjuvant therapy in NMIBC. Novel delivery mechanisms such as hyperthermia are interesting newcomers.


Introduction
Bladder cancer (BC) is the second most frequent urological malignancy affecting 573,000 patients worldwide each year [1].More than 75% of patients diagnosed with bladder cancer have a cancer confined to the mucosa or the lamina propria [2].
The standard treatment for NMIBC is transurethral resection of the bladder tumors (TURBT) followed by additional adjuvant treatment, which comprises single-shot intravesical chemotherapy dose induction +/− maintenance chemotherapy for up to three years [3][4][5].For low-risk tumors, single instillations of drugs such as postoperative Mitomycin C (MMC), Epirubicin (EPI), or Gemcitabine (GEM) have been found to be effective in reducing disease recurrences [6].Another meta-analysis study indicated that combined intravesical chemotherapy therapy after TURB is superior to TURB alone in reducing the recurrence rate of NMIB [7].
For intermediate, high-risk, and very high-risk bladder tumors, the most effective adjuvant therapy is with Bacillus Calmette-Guérin (BCG) [8].BCG therapy is typically given as a series of six weekly instillations followed by a maintenance regimen for up to 3 years.
In the cases of BCG being ineligible or patients being unresponsive, or in the case of BCG shortage, there are some chemotherapeutical agents available such as EPI, MMC, or GEM for intravesical instillations [9], at least six times weekly, but a fixed regimen has been not established yet.A full-year regimen is nowadays considered the minimum for best efficacy of the drugs (six weekly instillations followed by instillation at 6-week intervals for a year) [10].However, shared decision-making regarding adjuvant therapy with the patient relies also on various factors, including age [11], stage, grade, and risk stratification of bladder cancer, as well as individual patient characteristics such as sarcopenia [12].
As a treatment for bladder cancer, EPI still has a wide spectrum of use in many countries and geographical areas due to its therapeutic efficacy for NMBIC and lack of alternative approved treatments; on the other hand, in other countries such as the US, it is not approved for intravesical treatment [13].According to European Association of Urology (EAU) guidelines, EPI is an option in patients unfit for BCG or in the case of BCG shortage [2].In the US alone, it is estimated that more than 8000 patients are not receiving BCG due to a global shortage [14].So, as alternative adjuvant therapy after TURBT for bladder tumors, EPI has shown time-effectiveness in reducing recurrences.EPI works by interfering with the DNA of cancer cells, preventing their replication and growth [15].Given the prevalence of non-muscle invasive bladder cancer (NMIBC) and the importance of effective adjuvant therapies, our study aimed to comprehensively assess the efficacy and toxicity profile of Epirubicin (EPI).Specifically, we sought to investigate the recurrence-free survival (RFS) and progression-free survival (PFS) rates associated with EPI treatment compared to those of Bacillus Calmette-Guérin (BCG), Mitomycin C (MMC), and Gemcitabine (GEM).Additionally, we aimed to evaluate the impact of incorporating hyperthermia alongside EPI treatment, particularly in contrast to hyperthermia combined with MMC.Through this analysis, we aimed to provide clinicians and researchers with a clearer understanding of the comparative effectiveness and safety of EPI, as well as the potential benefits of hyperthermia augmentation in NMIBC management.

Materials and Methods
A systematic search of the MEDLINE, WebofScience, clinicaltrials.gov,and GoogleScholar databases was performed on 31 December 2023, using any combination of the following terms: Epirubicin (EXP) AND bladder cancer (EXP) OR Epirubicin (EXP) AND non-muscle invasive bladder cancer (EXP).All original articles that fulfilled the inclusion criteria were included.We performed additional cross-checking of the reference lists, and "hand searched" for any additional references.
Studies were considered eligible if they included patients with NMIBC; had a prospective or retrospective design; included at least 10 patients; and assessed the oncological impact of EPI treatment compared with those after BCG, MMC, and GEM or EPI standard treatment alone or using chemohyperthermia.The language of publication was not an exclusion criterion.The primary outcomes were a comparison of recurrence and progression rates between EPI and MMC, GEM, or BCG.The secondary outcome was to evaluate the safety profile of EPI and the impact of using device-assisted intravesical administration of EPI.For each selected study, the following items were recorded: first author's name, year of publication, country, study design, number of patients, patient's characteristics, variables included in multivariable analysis, recurrence rate, progression rate, follow-up, and adverse events (AEs), when reported.The study was conducted following the necessary protocols for research.Two investigators, S.C. and M.F.(the first two authors), independently conducted literature searches and extracted data from the full-text articles.In case of any discrepancies, these were resolved through consensus, involving a third investigator, M.D.V. (the corresponding author).

Adverse Events after Intravesical Instillations with Epirubicin
Eleven studies reported adverse events after adjuvant intravesical instillations with EPI, using a regimen of at least six weekly instillations.They included 1165 patients in total, of which 207 were females.The instillation regimen was not uniform as it has no clear recommendation and varied from 6 installations to 17 instillations [16][17][18].The most frequently reported adverse events were cystitis (34%), followed by dysuria, pollakiuria, hematuria, bladder irritation/spasms, fever, nausea and vomiting, and generalized skin rash (2.3%) [19]; see Table 1.

EPI versus MMC
Two studies [25,26] had investigated the effect of EPI compared to that of MMC, and they showed that there is no significant differences between the two drugs (EPI vs. MMC) regarding progression and recurrence; see Table 3.

EPI versus GEM
Two studies [27,28] had investigated the effect of EPI compared to that of GEM.They included 459 patients, of which 135 were female.Zhang et al. [28] (This reference was retracted) has shown a statistical significance of low recurrence and progression in patients with high-risk NMBIC, treated with GEM with anHR of 0.165, 95% CI 0.069-0.397,p = 0.000, for recurrence and an HR of 0.160, 95% CI 0.032-0.799,p = 0.026 for progression.On the other hand, Wang et al. [27] found no statistical significance regarding recurrence and progression; see Table 4.

Chemohyperthermia with Epirubicin
Chiancone et al. [29] looked at the oncological results of EPI as an adjuvant treatment using hyperthermic intravesical chemotherapy (HIVEC) administration.They included 26 patients, of which 18 were males and 8 were females.Recurrence occurred in two patients (7.69%) from the high-grade group and in one (3.85%)from low grade group, and two patients (7.69%) had progression.They concluded that EPI with HIVEC is a valid option of treatment for high-grade NMBIC with BCG intolerance, and there was no difference in oncological outcomes compared to MMC.Similar results were reported also by Arends et al. [30] when using the Synergo device to administer EPI or MMC into the bladder; see Table 5.

Discussion
The findings from studies investigating adverse events associated with intravesical instillations of Epirubicin (EPI) highlight several key points.Firstly, a substantial number of patients (1165) were included in 11 studies, indicating a robust data set for analysis.The incidence of adverse events varied, with cystitis being the most frequently reported adverse event (34%), followed by dysuria, pollakiuria, hematuria, and others [25,31].After gemcitabine, the most reported cases were nausea/vomiting (44.2%) and constipation/diarrhea (23.4%) [32].This underscores the importance of closely monitoring patients undergoing EPI treatment for non-muscle invasive bladder cancer (NMIBC) for these potential complications.
It is acknowledged that BCG treatment demonstrates superior efficacy in preventing disease progression, according to the data presented in the summary table of the analyzed studies (Table 2).The data were already confirmed by the meta-analysis of You et al. [31].
Regarding adjuvant chemotherapy, no clinically significant difference was observed between EPI, MMC, or GEM.The RFS and PFS rates are somewhat similar.However, a recent meta-analysis showed that among 22 studies adopting induction followed by maintenance intravesical therapy, regarding a lower dose of BCG, EPI was associated with a significantly higher risk of recurrence (odds ratio [OR]: 2.82, 95% CI: 1.54-5.15),but not other intravesical chemotherapies, with no significant differences in the risk of progression between intravesical therapies [32].Further prospective studies are needed to answer which drug has the best tolerability, safety, and impact on oncological outcomes.Some studies are already recruiting patients to test in vitro the drug with the highest antitumor efficacy [33].Until then, clinicians should use all available therapies based on shared decision-making with the patient and guideline recommendations.Regarding chemohyperthermia, there seems to be some benefit, but it is not yet quantifiable.
A recent randomized clinical trial (RCT) for MMC indicated that the recurrence-free survival (RFS) rate at 24 months was 61% (95% CI 51-69%) in the chemohyperthermiatreated group and 60% (95% CI 50-68%) in the control group (HR 0.92, 95% CI 0.62-1.37;log-rank p = 0.8) [34].These results should be interpreted considering that only the combat bladder recirculation system (Combat Medical, St. Albans, UK) was used for chemohyperthermia instillations, while many other systems are available for intravesical hyperthermia instillations [35], and their use may lead to different outcomes.Additionally, from all available data, no difference was observed in RFS estimates between patients treated with EPI and those treated with MMC [36].Concerning a comparison with the standard of care, which is BCG treatment, a recent meta-analysis showed no statistically significant difference between chemohyperthermia and BCG as the adjuvant treatment [37].However, there are little data on this question, and no solid conclusion can be drawn.
Overall, although EPI remains a viable option for the management of NMIBC, the results highlight the need for personalized treatment approaches based on individual patient characteristics and preferences.Further research is needed to elucidate the optimal use of EPI and potential synergies with other therapeutic modalities, including immunotherapy, to improve outcomes for NMIBC patients.

Conclusions
Epirubicin has meaningful efficacy in addressing NMIBC; however, its efficacy and indications are limited to selected patients, mainly with an intermediate risk according to EAU guideline stratification and to those unfit for or unresponsive to BCG therapy.Retrospective studies highlight that BCG stands out as more effective than Epirubicin in terms of preventing recurrence.Epirubicin exhibits similar oncological performances to Gemcitabine and Mitomycin C currently used for adjuvant therapy in NMIBC.Novel delivery mechanisms such as hyperthermia are interesting newcomers.

Table 1 .
Reported adverse events after intravesical instillation with Epirubicin.
30 mg of EPI plus 200 mg of Ara-C dissolved in 20 mL of physiological saline weekly for the first year, then every 2 weeks for the second year, once a month for the third year, and once every 3 months during the fourth and fifth years Severe, reversible cystitis 2 pts (4.5%) Legend: EPI: Epirubicin; TURBT: transurethral resection of bladder tumor, Ara-C: Cytosin Arabinoside.

Table 2 .
Studies comparing recurrence and progression rates after treatment with Epirubicin and Bacillus Calmete-Guerin.

Table 3 .
Studies comparing recurrence and progression rates after adjuvant treatment with Epirubicin or MMC in patients with non-muscle invasive bladder cancer.

Table 4 .
Studies comparing recurrence and progression rates after adjuvant treatment with Epirubicin or Gemcitabine in patients with non-muscle invasive bladder cancer.

Table 5 .
Studies comparing recurrence and progression rates after adjuvant treatment with Epirubicin or MMC using hyperthermia in patients with non-muscle invasive bladder cancer.